Adenosine A2 is an endogenous modulator, which among other effects mediates a general depression of the central nervous system, vasodilatation and inhibition of platelet aggregation.
Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. Up to now, four subtypes of adenosine receptors are known (i.e., A1, A2A, A2B (of high and low affinity) and A3 receptors). Adenosine receptors are all coupled to G-proteins; A1 and A3 subtypes are associated with inhibitory G-proteins and the A2A and A2B subtypes are associated with stimulatory G-proteins. Activation of the A1 and A3 receptors causes inhibition of adenylate cyclase and phospholipase C, which inhibits neurotransmission. The A1 receptors are highly expressed in the brain, especially in the hippocampus, thalamus, cerebellum and cortex compared to the A3 receptors which are moderately expressed in the brain. Activation of the A2A and A2B receptors causes activation of adenylate cyclase and phospholipase C, resulting in the stimulation of neurotransmission. A2A receptors are co-expressed in the brain with dopamine D2 receptors, especially in the striatum, olfactory tubercle and nucleus accumbens and are involved in neurodegenerative pathologies.
A2a receptors are densely distributed in the central nervous system (striatum, nucleus accumbens and olfactory tubercles) where they play an important role in the regulation of mood and motor activity (Poulsen, S. A., et al., Bioorg. Med. Chem., 1998, 6, 619; Ongini, E., et al., Trends Pharmacol. Sci., 1996, 17, 364). Parkinson's disease has been treated for more than thirty years by dopamine replacement strategies (Cotzias, G. C., et al., N. Engl. J. Med., 1969, 280, 337). However, because long-term use of dopamine-replacing agents is associated with severely disabling side effects, most notably dyskinesia (Chase T. N., Neurology, 1998, 50, S17-S25), non-dopaminergic treatments as monotherapies were judged as a promising strategy to treat such a disease (Brotchie, J. M., Curr. Opin. Neurol., 1997, 10, 340). Moreover, some scientific evidences also suggest that increased synthesis of adenosine A2a receptors in striatopallidal pathway neurons is associated with the development of dyskinesias following long-term levodopa therapy in Parkinson's disease (Calon, F., et al., Brain, 2004, 127, 1075; Xiao, D., et al., J. Neurosci., 2006, 26, 52, 13548). A2A antagonists, in association with a low dose of L-DOPA, displayed antiparkinsonian activity similar to that produced by a full dose of L-DOPA without exacerbating abnormal motor side effects (Tronci E., et al. Eur J. Pharmacol., 2007, 566, 94; Jenner P., Expert Opin. Investig. Drugs, 2005, 14, 6, 729).
Adenosine has also been implicated in numerous other pathologies such as epilepsy, cerebral ischaemic preconditioning, sleep and immune reaction within the brain (Brundege, J. M., et al., Adv. Pharma., 1997, 39, 353).
Imidazopyrimidine derivatives of formula A as antidiabetic compounds are disclosed in patent U.S. RE39,112 E (Eisai Co., Ltd.).
wherein R1 is

94% of the latter compounds (223 out of 237 exemplified compounds) present a fluoro-containing phenyl moiety as R3 group and/or a tertiary alcohol within the R1 radical, suggesting that those moieties constitute an important feature to confer the activity.
A patent (EP1412354) filed by the Applicant disclosed triazolyl-imidazopyridine and triazolylpurine derivatives endowed of anti-psychotic properties. However, none of the compounds of the present invention were neither disclosed nor suggested.